Genetic suppression of IKK2/NF-κB in astrocytes inhibits neuroinflammation and reduces neuronal loss in the MPTP-Probenecid model of Parkinson's disease.

Neuroinflammatory activation of glia is considered a pathological hallmark of Parkinson's disease (PD) and is seen in both human PD patients and in animal models of PD; however, the relative contributions of these cell types, especially astrocytes, to the progression of disease is not fully understood. The transcription factor, nuclear factor kappa B (NFκB), is an important regulator of inflammatory gene expression in glia and is activated by multiple cellular stress signals through the kinase complex, IKK2. We sought to determine the role of NFκB in modulating inflammatory activation of astrocytes in a model of PD by generating a conditional knockout mouse (hGfapcre/Ikbk2F/F) in which IKK2 is specifically deleted in astrocytes. Measurements of IKK2 revealed a 70% deletion rate of IKK2 within astrocytes, as compared to littermate controls (Ikbk2F/F). Use of this mouse in a subacute, progressive model of PD through exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp) revealed significant protection in exposed mice to direct and progressive loss of dopaminergic neurons in the substantia nigra (SN). hGfapcre/Ikbk2F/F mice were also protected against MPTPp-induced loss in motor activity, loss of striatal proteins, and genomic alterations in nigral NFκB gene expression, but were not protected from loss of striatal catecholamines. Neuroprotection in hGfapcre/Ikbk2F/F mice was associated with inhibition of MPTPp-induced astrocytic expression of inflammatory genes and protection against nitrosative stress and apoptosis in neurons. These data indicate that deletion of IKK2 within astrocytes is neuroprotective in the MPTPp model of PD and suggests that reactive astrocytes directly contribute the potentiation of dopaminergic pathology.

Is left ventricular hypertrophy a friend or foe of patients with aortic stenosis?

Left ventricular hypertrophy (LVH) is traditionally considered a physiological compensatory response to LV pressure overload, such as hypertension and aortic stenosis (AS), in an effort to maintain LV systolic function in the face of an increased afterload. According to the Laplace law, LV wall thickening lowers LV wall stress, which in turn would be helpful to preserve LV systolic performance. However, numerous studies have challenged the notion of LVH as a putative beneficial adaptive mechanism. In fact, the magnitude of LVH is associated with higher cardiovascular morbidity and mortality, especially when LVH is disproportionate to LV afterload. We have briefly reviewed: first, the importance of non-valvular factors, beyond AS severity, for total LV afterload and symptomatic status in AS patients; second, associations of excessive LVH with LV dysfunction and adverse outcome in AS; third, prognostic relevance of the presence or absence of pre-operative LVH in patients referred for aortic valve surgery; fourth, time course, determinants and prognostic implications of LVH regression and LV function recovery after surgical valve replacement and transcatheter aortic valve implantation (TAVI) with a focus on TAVI-specific effects; fifth, the potential of medical therapy to modulate LVH before and after surgical or interventional treatment for severe AS, a condition perceived as a relative contraindication to renin-angiotensin system blockade.